Rare Variant Enrichment Analysis Supports GREB1L as a Contributory Driver Gene in the Etiology of Mayer-Rokitansky-Küster-Hauser Syndrome

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, only WNT4 (MIM: 603490) variants have been definitively associated with a subtype of MRKH with hyperandrogenism (MIM: 158330). DNA from 148 clinically diagnosed MRKH probands across 144 unrelated families and available family members from North America, Europe, and South America were exome sequenced (ES) and by family-based genomics analyzed for rare likely deleterious variants. A replication cohort consisting of 442 Han Chinese individuals with MRKH was used to further reproduce GREB1L findings in diverse genetic backgrounds. Proband and OMIM phenotypes annotated using the Human Phenotype Ontology were analyzed to quantitatively delineate the phenotypic spectrum associated with GREB1L variant alleles found in our MRKH cohort and those previously published. This study reports 18 novel GREB1L variant alleles, 16 within a multiethnic MRKH cohort and two within a congenital scoliosis cohort. Cohort-wide analyses for a burden of rare variants within a single gene identified likely damaging variants in GREB1L (MIM: 617782), a known disease gene for renal hypoplasia and uterine abnormalities (MIM: 617805), in 16 of 590 MRKH probands. GREB1L variant alleles, including a CNV null allele, were found in 8 MRKH type 1 probands and 8 MRKH type II probands. This study used quantitative phenotypic analyses in a worldwide multiethnic cohort to identify and strengthen the association of GREB1L to isolated uterine agenesis (MRKH type I) and syndromic MRKH type II

Rare Variant Enrichment analysis Supports

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, onl

Screening for the genetic predisposition to obesity in the Greek population

Environmental and genetic components are involved in the development of complex disease of obesity. The aim of the present thesis was to investigate for the genetic predisposition to obesity in the Greek population. Analysis of 36 single nucleotide polymorphisms SNPs in 510 obese and 469 normal-weight individuals by using PRC-RFLPs, TaqMan assays and DNA sequencing as genotyping methods showed that 7 polymorphisms (rs1421085 in FTO gene, rs17782313 near MC4R gene, rs6548238 near TMEM18 gene, rs4712652 near PRL gene, rs2844479 near AIF1 gene, rs6234 in PCSK1 gene and rs6265 near BDNF gene) and one haplotype (QdelTG) of ENPP1 gene are associated with increased risk of obesity in Greeks. By using Real-Time PCR method, evaluation of expression levels of FTO and PRL genes in adipose tissue showed that their expression is tissue-depot specific (subcutaneous and visceral), depends on the metabolic state and is not affected from genetic variation. Furthermore, screening of MC4R gene for mutations detection by using DNA sequencing revealed that MC4R loss-of-function mutations are rare and could not explain high perentages of obesity in the Greek population. Finally, the role of SNPs in response of obese subjects to treatment with sibutramine and rimonabant (anti-obesity agents) was investigated. Analysis showed that polymorphisms in genes (GNB3, SLC6A2 and CNR1) involved in mechanism of drugs action do not affect weight loss after pharmaceutical intervention.Η παχυσαρκία είναι μια σύνθετη ασθένεια, στην εκδήλωση της οποίας συμβάλλουν τόσο περιβαλλοντικοί όσο και γενετικοί παράγοντες. Σκοπός της διατριβής ήταν η διερεύνηση της γενετικής προδιάθεσης για παχυσαρκία στον ελληνικό πληθυσμό. Με τις μεθοδολογίες PCR-RFLPs, TaqMan και ανάλυση πρωτοδιάταξης του DNA αναλύθηκαν 36 μονονουκλεοτιδικοί πολυμορφισμοί SNPs σε 510 παχύσαρκα άτομα και σε 469 άτομα φυσιολογικού βάρους και βρέθηκε ότι 7 πολυμορφισμοί (rs1421085 στο γονίδιο FTO, rs17782313 κοντά στο γονίδιο MC4R, rs6548238 κοντά στο γονίδιο TMEM18, rs4712652 κοντά στο γονίδιο PRL, rs2844479 κοντά στο γονίδιο AIF1, rs6234 στο γονίδιο PCSK1 και rs6265 κοντά στο γονίδιο BDNF) και ένας απλότυπος (QdelTG) του γονιδίου ENPP1 αυξάνουν σημαντικά τον κίνδυνο εμφάνισης παχυσαρκίας στους Έλληνες. Με τη μέθοδο της Real-Time PCR προσδιορίστηκαν τα επίπεδα έκφρασης των γονιδίων FTO και PRL στο λιπώδη ιστό και διαπιστώθηκε ότι η έκφραση τους ρυθμίζεται τοπικά σε κάθε αποθήκη λιπώδους ιστού (υποδόριο και σπλαγχνικό), εξαρτάται από την κατάσταση του μεταβολισμού και δεν μεταβάλλεται από την παρουσία γενετικής ποικιλομορφίας. Στη συνέχεια, πραγματοποιήθηκε σάρωση του γονιδίου MC4R για την ανίχνευση μεταλλάξεων με τη μεθοδολογία της ανάλυσης πρωτοδιάταξης και βρέθηκε ότι οι μεταλλάξεις, που οδηγούν σε απώλεια λειτουργίας του υποδοχέα MC4R, είναι σπάνιες και δεν μπορούν από μόνες τους να εξηγήσουν την υψηλή συχνότητα παχυσαρκίας στον ελληνικό πληθυσμό. Τέλος, ελέγχθηκε ο ρόλος πολυμορφισμών SNPs στην απόκριση παχύσαρκων ατόμων σε φαρμακευτική αγωγή με σιμπουτραμίνη και ριμοναμπάντη (ουσίες με αντι-παχυσαρκική δράση) και οι αναλύσεις έδειξαν ότι η ύπαρξη πολυμορφισμών σε γονίδια που εμπλέκονται στο μηχανισμό δράσης των φαρμάκων (γονίδια GNB3, SLC6A2 και CNR1) δεν επηρεάζουν την απώλεια βάρους ύστερα από φαρμακευτική παρέμβαση

Weight loss independent association of TCF7 L2 gene polymorphism with fasting blood glucose after Roux-en-Y gastric bypass in type 2 diabetic patients

Background: Roux-en-Y gastric bypass (RYGB) surgery improves glucose control in most but not all patients with type 2 diabetes mellitus (T2 DM). Transcription factor 7-like 2 (TCF7 L2) gene variation (rs790314O, C: wild-type allele, T: risk-allele) is the strongest contributor to T2 DM risk. Until now, there are no studies investigating gene interactions with changes of glycemia in obese patients with T2 DM after RYGB. The objective of this study was to assess the effect of TCF7 L2 genotype on RYGB-induced changes in glucose homeostasis in 99 obese patients with T2 DM at 1- year follow-up.Methods: Body mass index (BMI) and fasting blood glucose (FBG) were measured before and 1, 3, 6, and 12 months after RYGB. Genotyping was performed with TaqMan technology. The effect of the interaction between TCF7 L2 genotype and postoperative time on BMI and FBG changes was analyzed with a linear mixed model.Results: Preoperatively, there was no difference in BMI, FBG, and other diabetes associated traits between homozygous (CC) (n = 49) and heterozygous (CT) or homozygous (TT) T risk-allele carriers (n 50). One year after RYGB, 48 out of 99 patients had glycosylated hemoglobin (HbA1 c) lower than 6.5% in absence of any antidiabetic medication. BMI decreased similarly in both groups (P = .769, genotype-time interaction), however, the decrease in FBG over time was lower in T risk-allele carriers (P = .0 16, genotype-time interaction). At 1 year, FBG was 6.42 2.98 mmol/ L in CT/TT versus 5.36 0.98 mmol/L in CC (P = .022, t test).Conclusion: TCF7 L2 gene variation affected the decrease of FBG after RYGB in obese patients with T2 DM, independently of weight loss. (Surg Obes Relat Dis 2014:10:679 683.)

Socially Aware Heterogeneous Wireless Networks

The development of smart cities has been the epicentre of many researchers’ efforts during the past decade. One of the key requirements for smart city networks is mobility and this is the reason stable, reliable and high-quality wireless communications are needed in order to connect people and devices. Most research efforts so far, have used different kinds of wireless and sensor networks, making interoperability rather difficult to accomplish in smart cities. One common solution proposed in the recent literature is the use of software defined networks (SDNs), in order to enhance interoperability among the various heterogeneous wireless networks. In addition, SDNs can take advantage of the data retrieved from available sensors and use them as part of the intelligent decision making process contacted during the resource allocation procedure. In this paper, we propose an architecture combining heterogeneous wireless networks with social networks using SDNs. Specifically, we exploit the information retrieved from location based social networks regarding users’ locations and we attempt to predict areas that will be crowded by using specially-designed machine learning techniques. By recognizing possible crowded areas, we can provide mobile operators with recommendations about areas requiring datacell activation or deactivation

Cerebral Amyloidosis in Individuals with Subjective Cognitive Decline: From Genetic Predisposition to Actual Cerebrospinal Fluid Measurements

The possible relationship between Subjective Cognitive Decline (SCD) and dementia needs further investigation. In the present study, we explored the association between specific biomarkers of Alzheimer’s Disease (AD), amyloid-beta 42 (Aβ42) and Tau with the odds of SCD using data from two ongoing studies. In total, 849 cognitively normal (CN) individuals were included in our analyses. Among the participants, 107 had available results regarding cerebrospinal fluid (CSF) Aβ42 and Tau, while 742 had available genetic data to construct polygenic risk scores (PRSs) reflecting their genetic predisposition for CSF Aβ42 and plasma total Tau levels. The associations between AD biomarkers and SCD were tested using logistic regression models adjusted for possible confounders such as age, sex, education, depression, and baseline cognitive test scores. Abnormal values of CSF Aβ42 were related to 2.5-fold higher odds of SCD, while higher polygenic loading for Aβ42 was associated with 1.6-fold higher odds of SCD. CSF Tau, as well as polygenic loading for total Tau, were not associated with SCD. Thus, only cerebral amyloidosis appears to be related to SCD status, either in the form of polygenic risk or actual CSF measurements. The temporal sequence of amyloidosis being followed by tauopathy may partially explain our findings

Identifying novel regulatory effects for clinically relevant genes through the study of the Greek population

Abstract Background Expression quantitative trait loci (eQTL) studies provide insights into regulatory mechanisms underlying disease risk. Expanding studies of gene regulation to underexplored populations and to medically relevant tissues offers potential to reveal yet unknown regulatory variants and to better understand disease mechanisms. Here, we performed eQTL mapping in subcutaneous (S) and visceral (V) adipose tissue from 106 Greek individuals (Greek Metabolic study, GM) and compared our findings to those from the Genotype-Tissue Expression (GTEx) resource. Results We identified 1,930 and 1,515 eGenes in S and V respectively, over 13% of which are not observed in GTEx adipose tissue, and that do not arise due to different ancestry. We report additional context-specific regulatory effects in genes of clinical interest (e.g. oncogene ST7) and in genes regulating responses to environmental stimuli (e.g. MIR21, SNX33). We suggest that a fraction of the reported differences across populations is due to environmental effects on gene expression, driving context-specific eQTLs, and suggest that environmental effects can determine the penetrance of disease variants thus shaping disease risk. We report that over half of GM eQTLs colocalize with GWAS SNPs and of these colocalizations 41% are not detected in GTEx. We also highlight the clinical relevance of S adipose tissue by revealing that inflammatory processes are upregulated in individuals with obesity, not only in V, but also in S tissue. Conclusions By focusing on an understudied population, our results provide further candidate genes for investigation regarding their role in adipose tissue biology and their contribution to disease risk and pathogenesis

PROTEIN AI Advisor: A Knowledge-Based Recommendation Framework Using Expert-Validated Meals for Healthy Diets

AI-based software applications for personalized nutrition have recently gained increasing attention to help users follow a healthy lifestyle. In this paper, we present a knowledge-based recommendation framework that exploits an explicit dataset of expert-validated meals to offer highly accurate diet plans spanning across ten user groups of both healthy subjects and participants with health conditions. The proposed advisor is built on a novel architecture that includes (a) a qualitative layer for verifying ingredient appropriateness, and (b) a quantitative layer for synthesizing meal plans. The first layer is implemented as an expert system for fuzzy inference relying on an ontology of rules acquired by experts in Nutrition, while the second layer as an optimization method for generating daily meal plans based on target nutrient values and ranges. The system’s effectiveness is evaluated through extensive experiments for establishing meal and meal plan appropriateness, meal variety, as well as system capacity for recommending meal plans. Evaluations involved synthetic data, including the generation of 3000 virtual user profiles and their weekly meal plans. Results reveal a high precision and recall for recommending appropriate ingredients in most user categories, while the meal plan generator achieved a total recommendation accuracy of 92% for all nutrient recommendations

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes(1-4). Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases(3,5-13). GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference(5,6,14-16). Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents